Preparation of drug particles using evaporation precipitation into aqueous solutions

ABSTRACT

A method for preparing poorly water soluble drug particles is disclosed. The method comprises dissolving a drug in at least one organic solvent to form a drug/organic mixture, spraying the drug/organic mixture into an aqueous solution and concurrently evaporating the organic solvent in the presence of the aqueous solution to form an aqueous dispersion of the drug particles. The resulting drug particles are in the nanometer to micrometer size range and show enhanced dissolution rates and reduced crystallinity when compared to the unprocessed drug. The present invention additionally contemplates products and processes for new drug formulations of insoluble drug particles having high dissolution rates and extremely high drug-to-excipient ratios.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/266,998filed Oct. 8, 2002, which is a continuation-in-part of U.S. applicationSer. No. 09/808,332 filed on Mar. 3, 2001 which claims priority to U.S.application Ser. No. 60/245,479 filed on Nov. 3, 2000, under Title 35 ofthe United States Code section 120.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to drug particles and methods for theirpreparation. More particularly, the present invention relates to thepreparation of drug particles utilizing evaporative precipitation intoaqueous solutions.

STATEMENT OF FEDERALLY FUNDED RESEARCH

None.

INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC

None.

BACKGROUND OF THE INVENTION

Bioavailability is a term meaning the degree to which a drug becomesavailable to the target tissue after being administered to the body.Poor bioavailability is a significant problem encountered in thedevelopment of pharmaceutical compositions, particularly thosecontaining an active ingredient that is poorly soluble in water. Poorlywater soluble drugs tend to be eliminated from the gastrointestinaltract before being absorbed into the circulation.

It is known that the rate of dissolution of a particulate drug canincrease with increasing surface area, that is, decreasing particlesize. Efforts have been made to control the size and size range of drugparticles in pharmaceutical compositions. For example, wet millingtechniques have been used, as described in U.S. Pat. No. 5,145,684.However, such wet milling techniques exhibit problems associated withcontamination from the grinding media. It is difficult to produce highlyuniform submicron particles with wet milling and solids milling, andhandling can be time consuming. Large amounts of surfactants are neededfor stabilization resulting in small drug-to-excipient ratios. Moreover,exposing a drug substance to mechanical shear or high temperatures forprolonged periods can cause the drug to lose its activity.

Spray drying into vapor is another method used to form micron sized drugparticles. Spray drying is used commonly to formulate dry pharmaceuticalpowder, in most cases, either hydrophilic drugs in aqueous solution orpoorly water soluble drugs in organic solution are sprayed, whichapproaches do not offer a means to simultaneously spray a poorly watersoluble drug and water soluble excipient.

U.S. Pat. No. 5,985,248 teaches dissolving a hydrophilic excipient, orstabilizer, and a hydrophobic drug in a cosolvent system such aswater:ethanol, and spray drying the system into vapor. U.S. Pat. No.6,001,336 teaches suspending a hydrophobic drug in an aqueous solutioncontaining a hydrophilic stabilizer, and spray drying the suspensioninto vapor. U.S. Pat. No. 6,077,543 and International ApplicationPublication No. WO 98/29096 teach atomizing an organic and an aqueoussolution together into a vapor. In all of these teachings, drugparticles in the micron size range are formed. It is difficult toproduce sub-micron particles by these technique due to growth of thedrug particles during the solvent evaporation. As the water evaporatesit will no longer solvate hydrophilic stabilizers. Solvation of thestabilizer is needed for it to be able to prevent growth of the drugparticles. As a result, growth of the drug particles is not likely to beinhibited by the stabilizer and the particle size is typically greaterthan 1 micron. Moreover, in all of these teachings, the precipitation ofsurfactant, or other excipient, and stabilizers occur simultaneously inthe coaxial nozzle, and it is much more difficult to control theparticle morphology. Furthermore, in all of these teachings, the usefulexcipients are sugars, salts, pectin and citric acid, which are not goodstabilizers for preventing growth of particles during the spray process.

U.S. Pat. Nos. 5,795,594 and 5,851,453 teach the use of compressed fluidantisolvents to form drug particles in the micron-size range. Thisprocess has been called Precipitation using Compressed Antisolvents(PCA), Solution-Enhanced Dispersion of Solids (SEDS) and SupercriticalAntiSolvent process (SAS). In most cases this process does not utilizewater due to the low solubility of water in compressed carbon dioxide,so that it is difficult to use water-soluble excipients with thisprocess. However, in some cases, this process is able to use water byflowing an organic drug solution, an aqueous solution and a secondorganic solvent such as ethanol into compressed carbon dioxide. Theethanol is needed to extract the water into the CO2 phase. In thisprocess it is difficult to control the particle size due to thecomplexity of the mixing of the three streams in the jet. Also, theparticles must be recovered from a high pressure vessel, and high ratiosof CO2 to drug are necessary. Moreover, as the water contacts CO2, thepH in the water reaches 3, which can be detrimental to drug stabilityand interactions with excipients.

Young et al., Rapid Expansion from Supercritical to Aqueous Solution toProduce Submicron Suspensions of Water-Insoluble Drugs, Biotechnol.Prog. 2000, 16, 402-407, teach the formation of poorly water solubledrug particles by rapid expansion of supercritical fluid solutions intowater, the supercritical fluid was carbon dioxide above its criticaltemperature. The solubility of drugs in carbon dioxide and othersupercritical fluids such as ethane and propane is typically very small.It is difficult to add water soluble stabilizers and excipients in sprayantisolvent processes (PCA, SAS or SEDS) into carbon dioxide due to thelow solubility of water in CO2. Reverchon E., Supercritical AntisolventPrecipitation of Micro-and Nano-particles, J. Supercrit. Fluid., 1999,15, 1-21. These antisolvent processes require large ratios of carbondioxide to drug and the use of a high pressure vessel for recovery ofproduct. Even when an aqueous and two organic solutions are sprayedthrough a coaxial nozzle, the process is subject to many of thelimitations discussed above for spray drying organic and aqueous phasesthrough coaxial nozzles. As the water dissolves into the ethanol-carbondioxide mixture, it is no longer available to solvate stabilizers toprevent particle growth. Therefore this process is limited to relativelyfew drugs.

It would be an advantage in the art of preparation of drug particles toprovide a method which allows for easy control of particle size andmorphology and which is applicable to a wide breadth of drug substances.

An additional challenge for poorly water soluble drugs is to achievehigh dissolution rates with a high drug-to-excipient ratio or highpayload. From a therapeutic point of view, drug formulations with highdrug-to-excipient ratios, or payloads, have many advantages. First, suchformulations allow an effective dose to be used to produce high levelsof local drug concentration with greater therapeutic efficiency. Second,high drug loading results in less coadministration of the excipients,thereby minimizing potential biological reaction to such excipients.Excipients are used to increase the dissolution rates of poorly watersoluble drugs. Known techniques use a drug to excipient ratio on theorder of 1:1, for example, the Nanocrystal technology of Elanpharmaceuticals.

Therefore, there remains a need for drug formulations and techniquesthat allow for enhanced drug potency leading to greater therapeuticefficiency for poorly water soluble drugs. Accordingly, achievingimmediate release with a high drug-to-excipient ratio is desirable.

SUMMARY OF THE INVENTION

In one aspect, the present invention is a method for preparing poorlywater soluble drug particles comprising the steps of dissolving a drugin at least one organic solvent to form a drug/organic mixture; sprayingthe drug/organic mixture into an aqueous solution; and concurrentlyevaporating the organic solvent in the presence of the aqueous solutionto form an aqueous dispersion of the drug particles.

In a second aspect, the present invention is poorly water soluble drugparticles having an average particle diameter of from 50 nanometers to20 microns, the drug particles being prepared by a process comprisingthe steps of dissolving the drug in at least one organic solvent to forma drug/organic mixture; spraying the drug/organic mixture into anaqueous solution; and concurrently or rapidly evaporating the organicsolvent in the presence of the aqueous solution to form an aqueousdispersion of the drug particles.

In another aspect, the present invention provides for drying orotherwise removing water or other excipients from the aqueous dispersionof drug particles. The drying may be accomplished by any known method ofremoving water or other excipient(s) from particles including, but notlimited to, lyophilization, vacuum drying, spray drying, or the like. Inanother aspect of the invention, water removed is facilitated prior todrying, such as for example and without limitation, by centrifugation,filtration, settling, anti-solvent or flocculating agent, a gelationagent, an adsorbent, a solid matrix or solid particles that theparticles adhere to, or the like.

Another aspect of the present invention provides poorly water solubledrug particles with high drug:excipient ratios; high dissolution rates;high potency; or high surface areas. In an exemplary case herein,formulation of such micron or sub-micron size drug particles wereproduced by evaporative precipitation into an aqueous solutioncontaining the excipient.

In certain aspects, the present invention utilizes evaporativeprecipitation into aqueous solutions (EPAS) to form micron to sub-micronsized drug particles, leading to increased bioavailability relative tolarger particles. The process of the present invention has applicabilityto a wide range of drug substances as several solvents may be chosen todissolve the drug. The ability to utilize poorly soluble drugs and watersoluble stabilizers/excipients offers the ability to form submicronparticles that have high dissolution rates in aqueous media. The presentinvention also offers the ability to better control the resultingparticle size and morphology relative to techniques described in theabove identified prior art. Moreover, the present invention oftenproduces particles having reduced crystallinity as compared to the bulk,unprocessed drug, which enhances dissolution.

BRIEF DESCRIPTION OF THE FIGURES

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a schematic diagram illustrating one embodiment of the processof the present invention.

FIG. 2 is a cross-sectional view of a vessel useful in the process ofthe present invention.

FIGS. 3-4 are graphs showing improved dissolution rates for particles ofthe present invention.

FIG. 5 is an SEM showing reduced crystallinity of the particles of thepresent invention.

FIG. 6 is a graph showing improved dissolution rates for particles ofthe present invention.

FIG. 7 is a depiction of an EPAS apparatus, where T is a thermocouple, Pis a pressure regulator, and H is a HPLC pump.

FIG. 8 is an x-ray profile of danazol systems.

FIG. 9( a) is a graph showing danazol systems with high dissolutionrates.

FIG. 9( b) is a graph showing danazol systems with low dissolutionrates.

FIG. 10 is a graph reflecting the particle redispersibility in thestability study period.

FIG. 11 is a graph showing the x-ray peak height of danazol samplesduring the stability study.

FIG. 12 is a graph depicting the surface area of danazol systems duringthe stability study.

FIG. 13( a) is a graphic illustration of the dissolution profile ofsystem danazol+PVP 40T+SDS during stability study.

FIG. 13( b) is a graphic illustration of the dissolution profile ofsystem danazol+PVP K-15 during stability study.

FIG. 13( c) is a graphic illustration of the dissolution profile ofsystem danazol+PVP 40T during stability study.

FIG. 14 are SEMs showing danazol samples.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

FIG. 1 is a schematic diagram illustrating one embodiment of anapparatus useful for the process of the present invention. As shown,tank 11 contains a drug/organic mixture.

The drug/organic mixture is formed by dissolving a drug in at least oneorganic solvent. The resulting drug/organic mixture can be a solution,an emulsion or a microemulsion.

The drug which can be used in the process of the present invention canbe any poorly water soluble drug. Suitable drug substances can beselected from a variety of known classes of drugs including, forexample, analgesics, anti-inflammatory agents, anthelmintics,antianginal agents, anti-arrhythmic agents, antibiotics (includingpenicillins), anticoagulants, antidepressants, antidiabetic agents,antiepileptics, antigonadotropins, antihistamines, antihypertensiveagents, antimuscarinic agents, antimycobacterial agents, antineoplasticagents, immunosuppressants, antithyroid agents, antiviral agents,anxiolytic sedatives (hypnotics and neuroleptics), astringents,beta-adrenoceptor blocking agents, blood products and substitutes,cardiacinotropic agents, contrast media, cortieosterioids, coughsuppressants (expectorants and mucolytics), diagnostic agents,diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonianagents), haemostatics, immunosuppressive cyclic oligopeptides,immunological agents, lipid regulating agents, muscle relaxants,parasympathomimetics, parathyroid calcitonin and biphosphonates,radio-pharmaceuticals, sex hormones (including steroids), anti-allergicagents, stimulants and anorexics, sympathomimetics, thyroid agents,vasidilators and xanthines. Preferred drug substances include thoseintended for oral administration and intravenous administration. Adescription of these classes of drugs and a listing of species withineach class can be found in Martindale, The Extra Pharmacopoeia,Twenty-ninth Edition, The Pharmaceutical Press, London, 1989. Morespecific examples of drug substances useful in the practice of thepresent invention include but are not limited to danazol, cyclosponine,nifedipine, carbamazepine, naproxen, triamcinolone and its salts,hydrocortisone and its salts, prednisone and its salts, phenylbutazone,betamethasone and its salts, dexamethasone and its salts, 17-βestradiol, ketoprofen, verapamil, ketoconazole, mefenamic acid, andmetronidazole.

The organic solvent into which the drug is dissolved can be any organicsolvent which dissolves the drug to an adequate level. Preferably, theorganic solvent dissolves the drug to a level of 0.1 weight percent ormore, and more preferably to a level of 1.0 weight percent or more. Theorganic solvent is advantageously immiscible with water. Suitableorganic solvents include diethylether, methylene chloride, ethylacetate, dimethylether, perfluoroalkanes and isomers thereof, partiallyfluorinated solvents with or without other functional groups, and otherorganic solvents with boiling points below approximately 70° C., andcombinations thereof.

In one embodiment, the drug/organic mixture further contains a particlestabilizer. Stabilization is defined herein to mean that the resultingdrug particles do not grow substantially, and do not crystallizeexcessively. In this regard, a particle stabilizer is defined herein tomean a substance that substantially inhibits particle growth andsubstantially inhibits crystallization of the drug particles. Theparticle stabilizer can be water soluble or organic soluble, although,if the particle stabilizer is water soluble, bioavailability may beenhanced to an even greater degree. Particle stabilizers can also act asabsorption enhancers in order to increase bioavailability of the drugparticles.

The particle stabilizer present in the organic can contribute tostabilization of the particle in the aqueous phase. Examples of particlestabilizers include phospholipids, surfactants, either low molecularweight or polymeric, vesicles, polymers, including copolymers andhomopolymers and biopolymers, and/or dispersion aids. The particlestabilizer can be nonionic, anionic, cationic or zwitterionic. Suitablesurfactants include gelatin, casein, lecithin, (phosphatides), gumacacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride,calcium stearate, glyceryl inonostearate, cetostearyl alcohol,cetomacrogol 1000, polyoxyethylene castor oil derivatives,polyoxyethylene sorbitan fatty acid esters, for example, thecommercially available Tweens, polyethylene glycols, copolymers ofpolyethylene glycol and polypropylene glycol, polyoxyethylene stearates,colloidal silicon dioxide, phosphates, sodium dodecylsulfate,carboxymethicellulose calcium, carboxymethylecellulose sodium,methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulo-se phthalate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinylalcohol, sodiumlauryl sulfate.(SLS), polyvinylpyrrolidone (PVP), bile salts.

Referring again to FIG. 1, the drug/organic mixture is fed through feedline 12 to a sprayer, where the drug/organic mixture is sprayed into anaqueous solution contained in tank 13. The drug/organic mixture issprayed at or below the liquid level of the aqueous solution in tank 13.

In one alternative embodiment of the present invention, a portion of theaqueous solution can be sprayed together with the drug/organic mixtureinto the remaining portion of the aqueous solution. In such anembodiment, the nozzle should be designed so as to allow the spraying oftwo streams simultaneously. In such an embodiment, the level of theaqueous solution in tank 13 can be controlled by, for example, anoverflow, such that a continuous slurry of particles results. The slurryof particles can then undergo further processing to result in the finaldrug particles.

FIG. 2 is a cross-sectional view of tank 13 containing aqueous solution21. In a preferred embodiment, aqueous solution 21 contains at least oneparticle stabilizer. Suitable particle stabilizers include those listedabove for inclusion in the drug/organic mixture, the specific particlestabilizer or particle stabilizers selected for use in the aqueoussolution 21 can be the same or can be different from the particlestabilizer(s) in the drug/organic mixture. The weight ratio of drug tototal particle stabilizer is from 0.01:1 to 10:1, preferably from 0.05:1to 7:1 and more preferably from 0.1:1 to 4:1.

The drug/organic mixture is sprayed at or below the liquid level in tank13 through atomizer 22 to form a jet comprising droplets 23. The jetresults in intense mixing between the drug/organic mixture droplets andthe aqueous solution. Thus, as the drug/organic mixture is sprayedthrough atomizer 22, the organic solvent is concurrently evaporated intothe aqueous solution 21 to form an aqueous dispersion of the drugparticles. In this manner, evaporation of the organic solvent isoccurring rapidly with the spraying and stabilization of the drugparticles by the excipients in the aqueous solution. Evaporation of theorganic solvent occurs below the surface of the aqueous solution. Anexcipient is any substance combined with an active ingredient to preparea dosage composition. One example of an excipient is a surfactant whichis a compound that reduces the surface tension of liquids, or reducesthe interfacial tension between two liquids or a liquid and a solid.Excipients of the present invention may be used individually or incombination. In addition, excipients may be electrostatic or stearic orany combination of electrostatic and stearic.

Atomizer 22 can be any device that is capable of breaking up a bulkliquid into droplets. Suitable devices useful as atomizers includepressure nozzles, venturi nozzles, vibrating orifices, ultrasonic spraynozzles, rotating cups or disks, bubble caps or grids, or perforatedplates.

The atomization of the evaporating organic solution into small dropletsin the water and the intensity of the spray produce intense mixingbetween the growing drug particles and the water-soluble stabilizers andexcipients. The rapid evaporation of the organic solvent produces largesupersaturation of the drug and rapid precipitation. The rapidprecipitation of the drug has the potential to produce amorphous insteadof crystalline particles as the time frame is too short forcrystallization. The hydrophilic stabilizers remain solvated by waterduring the evaporation of the organic solvent. Thus, the stabilizerscover the growing drug particles and varying the flow rate, nozzlegeometry, concentration of drug and stabilizer and the nature of thestabilizer(s).

The temperature of the drug/organic mixture is at a level which allowsfor rapid evaporation of the solvent. Typically, this temperature willbe at least 50 degrees centigrade (° C.) below the normal boiling pointof the organic solvent to 80° C. above the normal boiling point of theorganic solvent. If the temperature of the drug/organic mixture is at orabove its normal boiling point, feed line 12 must be at sufficientpressure to maintain a liquid phase.

The temperature of the aqueous phase is preferably at least 10° C., morepreferably at least 50° C., and even more preferably at least 70° C. Theupper temperature limit will depend upon the operating pressure, but ispreferably low enough so as not to degrade the drug, but high enough toevaporate the solvent but not evaporate too much of the water. In apreferred embodiment, the temperature is less than 120° C., morepreferably less than 95° C., and even more preferably less than 85° C.The pressure of the aqueous solution can be at ambient pressure, belowambient pressure to facilitate evaporation or above ambient pressure.

In the present invention, the drug particles are produced in a liquidaqueous phase rather than a gas phase. Therefore, the particle growth isinhibited by aqueous stabilizers that do not precipitate. Thedissolution rates of the drug particles coated with water solublestabilizers may be expected to be high since the dispersions come froman aqueous phase. In the present invention the particle formation stageis distinct from stage in which the aqueous solution is dried. Thereforethe present invention can provide greater control over particle size.

The average particle diameter of the particles in the aqueous dispersionare from 50 nanometers to 20 microns, more preferably from 100nanometers to 5 microns, and even more preferably from 200 nanometers to1 micron. The drug particles are not necessarily spherical. Averageparticle diameter can be measured using any technique known to thoseskilled in the art, such as sedimentation field flow fractionation,photon correlation spectroscopy, disk centrifugation or dynamic lightscattering techniques.

An advantage of the present invention is the narrow polydispersity, alsoreferred to as particle size distribution, that results. The particlesize distribution is typically monomodal, with narrow size ranges.

As an additional advantage, it is believed that drug particles preparedaccording to the present invention can exhibit reduced crystallinity ascompared to the bulk, unprocessed drug. Such reduced crystallinity canlead to increased dissolution rates and bioavailability.

The process of the present invention desirably further comprises thestep of recovering the drug particles. In one embodiment, recovering thedrug particles comprises removing the water from the particles. Removingthe water can be performed using any technique known to those skilled inthe art, including spray drying, spray freeze drying, gellation, definedas gelling the particles within a polymeric matrix, lyophilization,drying with cold air, and filtration.

Advantageously, excipients can be added to either the drug/organicmixture or to the aqueous solution, either before or after the drugparticles are formed, in order to enable the drug particles to behomogeneously admixed for appropriate administration. Suitableexcipients include polymers, absorption enhancers, solubility enhancingagents, dissolution rate enhancing agents, stability enhancing agents,bioadhesive agents, controlled release agents, flow aids and processingaids. More particularly, suitable excipients include cellulose ethers,acrylic acid polymers, and bile salts. Other suitable excipients aredescribed in detail in the Handbook of Pharmaceutical Excipients,published jointly by the American Pharmaceutical Association and ThePharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986.Such excipients are commercially available and/or can be prepared bytechniques known in the art.

An additional embodiment of the present invention involves poorly watersoluble drug particles having high dissolution rates; highdrug-to-excipient ratios; high potency; or high surface area. Thedissolution rate, according to this invention, is the time necessary toachieve a percentage of particle dissolution at a rate faster than thatachieved by the bulk drug under similar conditions, where the bulk drugis approximately 99% pure without excipients. Dissolution rates,according to this invention, are greater than about 70%; perhaps greaterthan 80%; preferably greater than 90%; more preferably greater than 95%;and most preferably 100% of the drug particles dissolved within a periodof time 3 times faster than that of the bulk drug. Alternatively suchdissolution rates may be obtained within a period of time about 5 or 7times faster; preferably within a period of about 10 or 15 times faster;more preferably within a period of about 20 or 25 times faster; mostpreferably within a period of 30 times faster; and perhaps even fasterwhen compared to that of the bulk drug. Exemplary dissolution profilesare depicted at FIGS. 13( a)-(c).

The poorly water soluble drug particles of the present invention canpossess a drug-to-excipient ratio of about 2:1, although it ispreferable for the drug-to-excipient ratio to be 3:1 or greater, morepreferably about 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or greater, and mostpreferably about 10:1 or perhaps even greater.

In an alternative aspect, the present invention provides poorly watersoluble drug particles that are highly potent, where potency isexpressed as a percentage (wt. drug/(wt. drug+wt. excipient)). Thepotent particles of this invention have a potency of greater than about50%, and perhaps about 66% or greater, preferably greater than about 70%or 75%, more preferably greater than about 80%, 83%, 85% or 87%, mostpreferably greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, or 100%.

Another aspect of the present invention provides poorly water solubledrug particles that possess high surface area. The surface areasexhibited by particles of this invention are greater than about 2.5m²/g, perhaps even greater than about 5 m²/g, preferably greater thanabout 10 m²/g, more preferably greater than about 20 m²/g, and mostpreferably greater than about 30 m²/g.

The poorly water soluble drug particles of the present invention can beamorphous, crystalline or semi-crystalline. Amorphous meaning primarilyamorphous in structure, crystalline meaning primarily crystalline instructure and semi-crystalline meaning any mixture of amorphous andcrystalline domains.

The disclosed poorly water soluble drug particles can be produced by anymethod including solution precipitation, spray processes, wet milling,mechanical milling, anti-solvent based precipitation, or other methodsin which atomization of drug particles and excipient adsorption areemployed. While any technique may be utilized, spray freezing orevaporative precipitation into an aqueous solution is the preferredmethod.

In another aspect the present invention provides a broad range of liquiddosage form pharmaceutical composition made from the disclosed poorlywater soluble drug particles including those produced by the methodsdisclosed herein. Specifically, the present invention includes any ofthe disclosed poorly water soluble drug particle dispersions, combinedwith any pharmaceutically appropriate excipients, for delivery to asubject. Appropriate pharmaceutical excipients include particlestabilizers, tonicity adjusters, buffers, surfactants, mucoadhesiveagents, viscosity adjusting agents and other excipients that are knownin the art to prepare dispersions for pharmaceutical administration.Specific liquid or similar dosage forms that are contemplated includenebulization, parenteral, topical creams, emulsions, lotions and thelike, or transdermal administration forms. Specifically parenteraladministration routes contemplated include dispersions administeredintraveneously, intramuscularly, subcutaneously, intradermally,intrathecally, and may additionally comprise buffers, tonicity agents,biodegradable polymers, preservatives and other excipients that areknown in the art to prepare dispersions suitable for parenteraladministration. Moreover, it is contemplated that the dispersions may beadministered as an oral liquid, and comprise flavoring agents,sweetening agents, bulking agents, buffers, preservatives, tonicityadjusting agents, particle stabilizers, agents to modify the zetapotential and other excipients that are known in the art to preparedispersions for oral administration. As a liquid, no reconstitution isrequired. In addition, dispersions according to the invention may beformulated for administration topically to the eye to treat surface orintraocular conditions, and may comprise buffers, preservatives,tonicity adjusting agents, particle stabilizers, viscosity modifiers andother excipients that are known in the art to prepare dispersions forapplication to the eye. Also, the dispersions contemplated herein may beformulated for administration topically to the skin, surface of the eye,ear, nasally, vaginally or rectally as an ointment, cream or gel, andmay comprise buffers, preservatives, tonicity adjusting agents, particlestabilizers, viscosity modifiers and other excipients that are known inthe art to prepare dispersions for application to the area. It isfurther contemplated that the dispersion may be formulated foradministration in a transdermal patch comprising adding the dispersionwith polymers, gelling agents, absorption enhancing agents, particlestabilizers, adhesive agents and other excipients.

While the invention is described herein primarily in connection with itspreferred utility, i.e., with respect to micro and nanoparticulate drugsubstances for use in pharmaceutical compositions, it is also believedto be useful in other applications such as the formulation ofparticulate cosmetic compositions and the preparation of particulatedispersions for use in image and magnetic recording elements.

The following examples are for illustrative purposes only and are notintended to limit the scope of the claimed invention. Percentages are inweight percents unless otherwise stated.

EXAMPLES

For the following examples, the apparatus shown in FIG. 1 is used. Thedrug/organic mixture was fed via a Constametric 3200 HPLC pump through apreheating coil into a 30 mL receiving tank containing the requiredamount of aqueous solution. The nozzle used for the spraying was made bycutting 1/16″ stainless steel tubing to form an elliptical conicalgeometry at the end. The end of the tube was filed to obtain the desiredflow rate. Nitrogen was continuously flowed downward to break up foam incases where it formed. For all of the examples, particle size wasmeasured by dynamic light scattering techniques within 4 hours of thespray.

Dissolution testing for the following examples was carried out using aVankel dissolution apparatus following the USP Apparatus II paddlemethod. During all dissolution tests, to ensure sink conditions, only10-30 percent of the saturation solubility of the drug was added to thedissolution apparatus. The appropriate amount of final drug preparationwas weighed and added to 900 ml of distilled water. Each sample wasstirred at 50 rpm using a paddle-type stirrer. The dissolution apparatuswas maintained at 37° C. throughout the experiment. Samples in theamount of 5 ml were automatically withdrawn at 10, 20, 30 and 60 minuteintervals. These samples were filtered using a 0.45 μm filter (GelmanOHP Acrodisc 0.45 μm, VWR). To ensure that no precipitation occurredduring HPLC analysis, 0.5 ml of organic solvent was added to 3 ml offiltered sample. This organic solvent was preferably the organiccomponent in mobile phase (acetonitrile). These were mixed using avortex mixer at high speed for approximately 10 seconds and thenrefiltered using a 0.45 μm filters into a HPLC vial for analysis. HPLCanalysis was different for each drug and the exact methods beingmodified from those suggested in ‘HPLC methods for pharmaceuticalanalysis’ by George Lunn and Norman R. Schmuff, John Wiley & Sons, NY,1997.

Examples 1-8

The drug was cyclosporine, the organic was diethylether, and theconcentration of the drug/organic mixture was 5.0 weight percentcyclosporine in diethylether. For the aqueous solution, Tween-80, apolyoxyethylene sorbitan monolaurate (ACROS) was a surfactant, or otherexcipient, which was used as the particle stabilizer. The drug/organicmixture was sprayed into 10 mL of aqueous solution at a rate of 1ml/min. Table A lists processing parameters and the resulting particlesizes.

TABLE A Drug/ organic Aqueous Spray Tween-80 Median percent temp. temptime conc (wt particle particles < Ex (° C.) (° C.) (min) percent) size(nm) median size 1 65 55 10 1 470 11 2 65 55 10 1 608 64 3 65 65 10 11114 61 4 65 65 10 1 759 41 5 70 65 10 1 706 33 6 70 65 10 1 796 43 7 7065 10 1 932 50 8 70 65 20 5 322 14

Examples 9-13

The drug was cyclosporine, the organic was diethylether, and theconcentration of the drug/organic mixture was as shown below in Table B.For the aqueous solution, phosphatidyl choline (10 wt percent), a Sigmaegg lecithin, 60 percent pure, was a surfactant, or other excipient,used as a particle stabilizer. The drug/organic mixture was sprayed into10 mL aqueous solution at a rate of 1 ml/min. The temperature of theaqueous solution is 75° C., while the drug/organic mixture was sprayedinto the aqueous solution at a temperature of 75° C. Table B lists someprocessing parameters and the resulting particle sizes.

TABLE B Drug conc Drug conc in Spray in aqueous Particle size organicsoln time (mg/ml Drug/surfactant range Ex (wt percent) (min) water)ratio (nm) 9 1 20 14.5 0.13 135-390 10 2 19 30.8 0.28 120-575 11 5 1037.1 0.33  90-300 12 5 10 34.9 0.32 215-590 13 10 6 29.7 0.30 170

Examples 14-16

The drug was cyclosporune (5 wt percent), the organic solvent was thatlisted in Table C below. For the aqueous solution, Poloxamer 407(1 wtpercent), also known as Lutrol-F127, a poly(ethylene)-poly(propylene)block polymer consisting of 73 percent of polyethylene glycol and 27percent polypropylene glycol with an average molecular weight of 12,000(BASF), was a surfactant, or other excipient, used as a particlestabilizer. The drug/organic mixture was sprayed into 25 mL aqueoussolution at a rate of 1 ml/min. The temperatures of the aqueous solutionand of the drug/organic mixture were 75° C. Table C lists someprocessing parameters and the resulting particle sizes.

TABLE C Drug conc in aqueous (mg/ml Drug/surfactant Particle size ExOrganic Solvent water) ratio range (nm) 4 Diethyl Ether 15 1.5  320-100015 Dichloromethane 17.8 1.78 160-345 16 Dichloromethane 14.8 1.48196-202

Examples 17-21

The drug was danazol, and the solvent was methylene chloride. Theparticle stabilizer in the aqueous solution is listed below in Table D.In all cases, the concentration of the particle stabilizer in aqueoussolution was 1 weight percent. The drug/organic mixture (2 wt percentdrug) was sprayed into the aqueous solution at a rate of 2 ml/minute for5 minutes. The temperature of both the aqueous solution and thedrug/organic mixture was 75° C. The drug/excipient ratio was 1.06.

TABLE D Ex Particle stabilizer Particle size range (nm) 17 Sodium laurylsulfate 370-415 18 Poly (vinyl pyrolidone) 140-280 19 Poly (vinylpyrolidone) 315-450 20 Poloxamer >1000 21 *Myrj 52 >1000 *Myrj ispolyoxyethylene monostearate

Examples 22-26

The drug was Carbamazepune, and the solvent was methylene chloride. Theconcentration of drug in the organic was 2 weight percent. The particlestabilizer in the aqueous solution is listed below in Table E. In allcases, the concentration of the particle stabilizer in aqueous solutionwas 1 weight percent. The drug/organic mixture was sprayed into theaqueous solution at a rate of 2.5 ml/min. The temperature of both theaqueous solution and the drug/organic mixture was 75° C. Thedrug/excipient ratio was 1:30.

TABLE E Ex Particle stabilizer Particle size range (nm) 22 Sodium laurylsulfate (SLS) >7000 23 Poly (vinyl pyrolidone) (PVP)  320-1000 24Polyethylene glycol 290-550 25 Poloxamer >1000 26 Myrj 52 >1000

Examples 27-29

The drug was Triamcinolone acetonide, also referred to herein as TAA,and the solvent was methylene chloride. The concentration of drug in theorganic was 0.5 weight percent. The particle stabilizers in the aqueoussolution and the organic solution are listed in Table F. In all casesthe concentration of the particle stabilizer in the aqueous solution was1 Weight percent and in the organic solution was 0.5 weight percent. Thevolume of the aqueous Solution was 15 ml. In all cases the resultingaqueous drug suspension was poured into a Hydroxypropylmethyl cellulose(HPMC) (grade E-5), thoroughly mixed by hand, poured into a Glasscrystallization dish and vacuum dried for at least 10 hours attemperatures ranging from 40-60° C. and a vacuum level of 30 inches ofHg. The resulting solids were mechanically ground to a powder anddissolution studies were performed on these powders. The results ofthese dissolution tests were compared with that for bulk TAA. Theresults shown in FIG. 3 indicate the increased dissolution rates of TAAprocessed according to the present invention.

TABLE F Amount of HPMC added Ex Organic stabilizer Aqueous stabilizerfor gellation (g) 7 PVP K-15 Deoxycholic acid 3 28 Poloxamer 407 PVPK-15 2 29 Poloxamer 407 Deoxycholic acid 2

Examples 30-32

The drug was carbamazepine and the solvent was methylene chloride, thetemperature of the drug/organic mixture and the receiving aqueoussolution was 87° C. The concentration of drug in the organic was 1.0weight percent. The particle stabilizers in the aqueous solution arelisted in Table G. In all cases the concentration of the particlestabilizer in the aqueous solution was 2 weight percent and the organicsolution contains, in addition to the drug, 0.5 weight percent Poloxamer407. The volume of the aqueous solution was 20 ml. In all cases theresulting aqueous drug suspension was sprayed into liquid nitrogen andthe frozen particles were then lyophilized for 24 hours. The resultingpowder was thoroughly mixed and dissolution studies were performed onthese powders. The results of these dissolution tests were compared withthose for bulk carbamazepine. The results shown in FIG. 4 clearlyindicate the increased dissolution rates of carbamazepine processedaccording to the present invention over the bulk unprocessedcarbamazepine. The crystallinity of these powders was also studied, withthe result being a reduction in crystallinity as compared to the bulkdrug.

TABLE G Ex Aqueous stabilizer 30 Deoxycholic acid 31 PVPK-15 32 SLS

Example 33

The drug was carbamazepine and the solvent was methylene chloride. Thetemperature of the drug/organic mixture and the receiving aqueoussolution was 87° C. The concentration of drug in the organic was 1.0weight percent. The particle stabilizer in the aqueous solution was 2weight percent deoxycholic acid and that in the organic solution was 5weight percent Poloxamer 407. The organic solution was sprayed at 2ml/min for 27 minutes into 50 ml of the aqueous deoxycholic acidsolution. The suspension was immediately spray dried in a Buchi 190spray dryer where an inlet temperature of 145-150 degrees C. and anoutlet temperature of 90-95° C. were maintained. The resulting drypowder was collected, and an SEM micrograph of this powder is shown inFIG. 5. The Figure shows no crystalline particles indicating theamorphous nature of the drug produced using EPAS.

Examples 34-37

The drug was nifedipine and the solvent was methylene chloride. Theconcentration of drug in the organic was 1.0 weight percent. In allcases the stabilizer in the aqueous solution was poly(vinyl alcohol)(PVA). The volume of the aqueous solution was 20 ml. Table H listsexcipients added to the aqueous solution in addition to the PVA. In allcases the resulting aqueous drug suspension was rapidly frozen bydipping the sample container in liquid nitrogen and then lyophilized for24 hours. The resulting powder was thoroughly mixed and dissolutionstudies were performed on these powders. The results of thesedissolution tests were compared with that for bulk nifedipine. Theresults, shown in FIG. 6, clearly indicate the increased dissolutionrates of EPAS processed nifedipine over the bulk unprocessed nifedipine.The crystallinity of these powders was also studied using X-raydiffraction patterns, with the Result being a reduction in crystallinityof the drug processed according to the present invention as compared tothe bulk drug.

TABLE H Ex Excipients in aqueous solution 34 1.5 wt percent PVP K40 351.5 wt percent SLS 36 1 wt percent Poloxamer 407 37 1 wt percent PVP K15

Examples 38-39

The drug was ketoprofen and the solvent was methylene chloride. Thetemperature of the sprayed drug/organic mixture and the receivingaqueous solution was 87° C. The concentration of drug in the organic was1.0 weight percent. The particle stabilizers in the aqueous solution arelisted in Table 3. In all cases the concentration of the particlestabilizer in the aqueous solution was 2 weight percent and the organicsolution contains, in addition to the drug, 0.5 weight percent Poloxamer407. The volume of the aqueous solution was 20 ml. In all cases theresulting aqueous drug suspension was rapidly frozen by dipping thesample container in liquid nitrogen and then lyophilized for 24 hours.Crystallinity studies were performed on these powders using X-raydiffraction patterns, and were compared with that for bulk ketoprofen,which resulted in the processed powder exhibiting amorphous character asopposed to the bulk ketoprofen.

TABLE J Ex Aqueous stabilizer 38 Deoxycholic acid 39 SLS

Examples 40-45

Danazol particles with high dissolution rates and extremely highdrug:excipient ratios greater than about 5, corresponding to a potency(wt drug/wt drug+wt excipient) above 80% were produced by EPAS. Anaqueous suspension was produced by EPAS to produce surfactant, or otherexcipient, coated particles with a low drug:excipient ratio ranging from1:4 to 1:1. The suspension was then centrifuged and the supernatant wasdecanted to remove the free surfactant, or other excipient, in order toraise the potency in the precipitate. The adsorbed surfactant, or otherexcipient, was sufficient to prevent aggregation and enhance wetting tomaintain a high surface area and likely a high local equilibriumconcentration of API in the diffusion layer. The dissolution rate wasanalyzed as a function of the surfactant, or other excipient,adsorption, particle size, surface area, contact angle, particlemorphology and crystallinity.

Danazol was purchased from Spectrum Chemicals & Laboratory ProductsCorporation (Cat# D1103). Pluronic F127 (BASF), Polyvinylpyrrolidone(PVP K-15, Mw=15,000 and PVP 40T, Mw=40,000) (Sigma, St. Louis, Mo.),Sodium dodecyl sulfate (Sigma) and Deoxycholic acid (Sigma) were used asreceived. HPLC grade acetonitrile was from Merck (Germany) and spectrograde dichloromethane was from Fisher Scientific Co. (NJ, USA).

Evaporative Precipitation into Aqueous Solution (EPAS). The organicdanazol solution was fed by an HPLC pump through a 3 m long 1/16 in.o.d.times.0.030 in. i.d. stainless steel coiled tube contained within a11/2″ OD.times.24″ long plastic water jacket (Alltech). Water wascirculated through the jacket with a JULABO MP temperature controller.The organic solution was atomized through an unheated insulatedadjustable restrictor (5 mm dia.times.136 mm long, ISCO, USA) into hotwater. Atomization was achieved by adjusting the nozzle valve manuallyto maintain a pressure drop to about 3500 psi. The aqueous stabilizingsolution was contained in a 250 ml plastic submerged in atemperature-controlled water bath. The nozzle was submergedapproximately 10 cm under the surface of the aqueous solution. Tosuppress and drain the foam produced by the organic vapor, nitrogen wasblown downwards on top of the foam at 20 psi into the cylinder throughthree 1/16 in. o.d. times.0.030 in. i.d. stainless steel tubes. Unlessindicated otherwise, the stabilizer was added in the aqueous phase andwas not present in the organic feed solution. After spraying for arequired time to produce the desired drug/excipient ratio, thesuspension was recovered and analyzed within 30 mins to determine theparticle size by light scattering with a Malvern Mastersizer-S (MalvernInstruments Ltd., U. K.).

Excipient Adsorption Measurement. To quantify excipient stabilization ofthe danazol particles in the EPAS suspension, excipient adsorption wasmeasured based on a mass balance between the supernatant andprecipitate. In these measurements, W_(s), was the weight of thesupernatant before drying, which includes the weight of water, excipientand danazol, which may dissolve in micelles or excipient complexes ifformed. W_(sd) was the weight of the supernatant after drying, thus(W_(sw)-W_(sd)) was the amount of water in the supernatant. W_(sp), wasthe weight of the precipitate before drying, which includes danazol,adsorbed excipient and a small amount of supernatant with the samecomposition as the bulk supernatant. W_(pd) was the weight of theprecipitate after drying. W_(pdan) was the amount of danazol in theprecipitate measured by HPLC W_(psurf) was the amount of adsorbedexcipient on danazol. Since composition of the small amount ofsupernatant in the precipitate was assumed to be the same as that in thebulk supernatant

$\begin{matrix}{\frac{W_{sd}}{W_{sw} - W_{sd}} = \frac{W_{pd} - W_{p_{dan}} - W_{psurf}}{W_{pw} - W_{pd}}} & (1)\end{matrix}$

From this equation, the amount of adsorbed excipient on danazol wasgiven by

$\begin{matrix}{W_{psurf} = {W_{pd} - W_{pdan} - {\left( {W_{pw} - W_{pd}} \right) \times \left( \frac{W_{sd}}{W_{sw} - W_{sd}} \right)}}} & (2)\end{matrix}$

To measure the amount of excipient adsorbed on the particles, 1% w/vdanazol solution in dichloromethane was sprayed into 15 ml aqueoussolution containing 1% w/v excipient at a flow rate of 1 ml/min for 7.5mins to produce a suspension with a drug to excipient ratio of 0.5:1.The pressure drop was 3000-4000 psi and the temperature was 75° C. Aftercentrifugation, the supernatant and the precipitate were weighed beforeand after drying at 55° C. and −30 in. Hg.

High Potency Danazol Powder by Centrifugation. Two percent (2%) w/vdanazol solution in dichloromethane was sprayed at a flow rate of 1ml/min into 100 ml aqueous solution containing 1% w/v excipient or aexcipient mixture at 1:1 w/w ratio, if two surfactants were used, tostabilize the drug particles. The temperatures of both heating jacketand water bath were 80° C. and the pressure drop was 3500-4000 psi.After 25 minutes spray, a suspension with drug to excipient ratio of 0.5was recovered and the particle size of the danazol particles wasmeasured with Malvern Mastersizer-S. The suspensions were centrifuged(BECKMAN, Model TJ-6, USA) at 3000 rpm for 30 mins. The supernatantswere poured out and the precipitates were placed into a vacuum oven anddried at 40° C., and −30 in Hg for 3-4 hrs. The crystallinity of the drypowders was examined by x-ray diffraction (PW1720, PHILIPS). The surfacearea of the dry powders was measured with a high-speed surface area BETanalyzer (NOVA 2000, Quantachrome Instruments, USA).

Dissolution Test. After centrifugation and vacuum drying, 20 mg drypowder was placed into a USP basket assembly and stirred at 50 rpm in pH9.0 SDS/tris buffer, which contained 0.75 w/v % sodium dodecyl sulfateand 1.21 w/v % tris (hydroxymethyl) aminomethane PD 2960 in aqueoussolution for 1 hour. The stirring rate was then increased to 200 rpm for1 hour. Aliquots of the dissolution medium (5 ml) were sampled at 2, 5,10, 20, 30, 60 and 120 mins. The aliquots were filtered through 0.45 μmsyringe filters and 2 ml of each sample were diluted with 0.1 mlacetonitrile before analysis. Danazol concentrations were measured usingHPLC (SHIMADZU, LC-600, Japan).

Particle Size. Particle size distributions, based on volume fraction, ofthe original EPAS suspension and redispersed dry powder were measured bystatic light scattering with a Malvern Mastersizer-S. To measure theparticle size distribution, 5 ml suspension with 5 mg drug/ml waterconcentration, was diluted with 500 ml distilled water, to produce alight obscuration in the range of 10-30% for accurate measurement. Tostudy the redispersibility of the dry powders after centrifugation andvacuum drying, about 50 mg dry powder were suspended into 500 mldistilled water to produce an obscuration in the range 10-30%. After 1minute, the particle size distribution was measured. In a controlexperiment, bulk danazol was dispersed in 500 ml 0.02% nonmicelle-forming PVP 40T aqueous solution, since it was very hydrophobicand difficult to disperse in pure water. Ultrasound was used in themeasurement to break up the agglomerated particles.

Contact Angle. mg dry powder was filled into a 0.7 cm diameter flatfaced die and compressed with a Carver Laboratory Press (Model M, FredS. Carver Inc, WIS, USA) at 1500 kgf into a tablet. A drop of 51 μldistilled water was placed on the surface of the tablet and contactangle was measured from the tangential angle of the water drop with helpof a camera (Panasonic WV-1410, Philippines).

Stressed Cycle Stability Study. Dry powders were placed in 60 ml Qorpak®glass bottles, sealed with sodium calcium aluminosilicate hydratedesiccant containing cobaltous chloride indicator (VWR International,West Chester, Pa.). The temperature cycle was: increase temperature from−5° C. to 40° C. over 30 mins, hold at 40° C. for 2.5 hours and thendecrease temperature from 40° C. to −5° C. over 30 mins. The cycle wasrepeated 6 times per day. The humidity was dry and the duration of thestability study was 2 weeks. The characteristics of the dry powders werestudied over two weeks.

Excipient Adsorption Study. The adsorption of various surfactants ontodrug particle surfaces during EPAS are listed in Table K(1).

TABLE K(1) Adsorption of excipient onto danazol in EPAS suspensionAqueous M_(w) of W_(sf) /W_(d) excipient Properties Chemical structureof excipients excipients (m/m, %) PVP K- 15 Homopolymer

15,000 13.0 ± 2.43 PVP Homopolymer 40,000 10.0 ± 1.01 40T Pluronic F127Copolymer

12,528 3.87 ± 1.43 Pluronic Copolymer 12,528 11.2 ± 0.72 F127* DCAAnionic surfactant

414 5.79 ± 1.61 SLS Anionic CH₃(CH₂)₁₀CH₂O—SO₂—ONa 288 5.44 ± 0.46surfactant *Adsorption measurement after 3 days storage at ambientconditions.

TABLE K(2) Pluronic F127 adsorption on danazol particles after 3 daysstorage W_(sw) W_(sd) W_(pw) W_(pd) W_(pdan) W_(psur) W_(psur)/W_(pdan)(g) (g) (g) (g) (mg) (mg) (%) 1.8987 0.0414 0.1276 0.0200 15.820 1.88811.9 1.5594 0.0373 0.0901 0.0213 17.753 1.862 10.5 The recovery ofdanazol in the precipitate and its potency

Table M shows the concentration of danazol in the supernatant. For PVP40T and PVP K-15, the concentration of danazol in the supernatantsolution was on the order of the detection limit which was 0.02 μg/ml.The fraction of danazol in the aqueous suspension recovered in theprecipitate after centrifugation was above 99%. For Pluronic F127, SDSand DCA, the recoveries decreased, but were still greater than 96.2% foreach excipient except for SDS. After centrifugation and vacuum drying,the potency of danazol in the dry powders was higher than 83.2%, asshown in Table L. Drug:excipients ratios varied from 4:1 to 9:1.

TABLE L Particle size of danazol in the suspension at excipientconcentration was 1% w/v and its redispersibility after drying. D (v,0.5) D (v, 0.5) D (v, 0.5) (μm) (μm) (μm) redispersed EPAS suspensiondry powders Aqueous Excipients suspension with ultrasonic w/o ultrasonicBulk Danazol 29.63 21.07 (30 s) PVP K-15 29.47 15.27 (15 s) 14.15 12.50(30 s)  7.60 (30 s) PVP 40T 49.28 13.82 (15 s) 14.07 17.62 (30 s) 10.53(30 s) PVP40T + SLS 16.80 13.82 (30 s) 18.00 12.13 (30 s) Pluronic F12780.35 32.29 (15 s) 39.73 25.09 (30 s) 22.17 (30 s) DCA 100.09 24.64 (30s) 56.86 23.88 (30 s) SLS 70.62 31.65 (15 s) 61.14 27.50 (30 s) 29.32(30 s) PVP 40T + Pluronic F127 125.92 28.75 (30 s) 71.73 26.16 (30 s)PVP40T + DCA 121.77 28.02 (15 s) 52.90 23.61 (30 s) 23.23 (30 s)

TABLE M Concentration of danazol in the supernatant, recovery from theprecipitate and its potency (g danazol/g powder) in the dry powdersDanazol Potency C_(ds) recovery of danazol Aqueous excipient (mg/ml) (%)(%) PVP K-15 0.0002 100 88.5 PVP 40T 0.0001 100 92.3 Pluronic F127 0.03599.3 89.3 DCA 0.084 98.3 85.1 SLS 0.804 82.1 83.2 PVP 40T + PluronicF127 0.009 99.8 91.5 PVP 40T + DCA 0.020 99.6 86.4 PVP 40T + SLS 0.19196.2 92.9

Dissolution Rate

Dissolution Rate. As shown in FIGS. 9( a) and 9(b), the dissolution ratewas much higher for PVP K-15, PVP 40T or PVP 40T+SDS than the otherstabilizers. In two mins, 70, 80 and 90% danazol was dissolved with PVP40T, PVP K-15 or PVP 40T+SDS as the surfactants, respectively. For theother systems, the dissolution rates were much lower, closer to that ofbulk danazol. We will show below that these systems had larger particlesizes and lower surface areas.

The effect of adsorbed excipient and free excipient on dissolution ratewas studied by mixing PVP 40T precipitate from the centrifuged EPASsuspension with PVP 40T powder to form an overall drug to excipientratio of 0.5. As shown in FIG. 9( a), the dissolution rate did notchange. The changes in surface area, diffusion layer thickness andconcentration of the API in bulk solution from the EPAS spray andadsorbed excipient were sufficient to produce high dissolution rates,without any need for mixing in additional stabilizer powder.

Particle Size Distribution and Redispersibility of the Dry Powders. Themean particle sizes of the EPAS suspensions, EPAS suspensions aftersonication, and redispersed dry powders after centrifugation and vacuumdrying are shown in Table L. The particle sizes, both with and withoutsonication, are correlated with the adsorption during the EPAS spraygiven in Table K.

X-Ray Diffraction. X-ray diffraction was used to analyze thecrystallinity of the dry powders. As shown in FIG. 9, the crystallinityof danazol was lower for the vacuum dried precipitates from EPASrelatively to bulk danazol. The a-peak heights of danazol in differentexcipient systems at 20=15° are listed in Table N. The reduction incrystallinity was less than 20% after correction for the presence of 10%w/w excipient. It was assumed that the danazol peak height was linear inconcentration for a fixed weight. The degree of crystallinity for thesesamples did not appear to be correlated to the particle size ordissolution rates. Thus enhanced dissolution rates are possible evenwith only a modest reduction in crystallinity.

TABLE N The peak height of danazol x-ray diffraction at 2θ = 15°Excipient Peak height (counts) Bulk danazol 3182 PVP K-15 2358 PVP 40T1942 Pluronic F127 2843 DCA 2413 SLS 2867 PVP 40T + Pluronic F127 2546PVP 40T + DCA 2371 PVP 40T + SLS 2465

Surface Area

Surface Area. The BET surface areas of the dry powders were analyzed. Asshown in Table O, systems with small particle size and high dissolutionrates, that is danazol with PVP K-15, PVP 40T or PVP 40T+SDS, hadsurface areas on the order of 5 m²/g.

TABLE O Surface area of the dry powder Excipient Surface Area (m²/g)Bulk danazol 0.52 PVP K-15 5.55 PVP 40T 4.89 PVP 40T + SLS 4.98 PluronicF127 3.13 DCA 3.72 SLS 3.07 PVP 40T + Pluronic F127 3.28 PVP 40T + DCA3.22

Contact Angle

Contact Angle. The contact angle results are shown in Table P. Forsystems with high dissolution rates, contact angles were close to thevalue of pure PVP, which was 43°, indicating high surface coverage byPVP. For the anionic excipient systems, the contact angles were verylow. The overall contact angle may be written as

cos θ=f ₁ cos θ₁ +f ₂ cos θ₂

where f₁ and f₂ are the fractions of the surface occupied by surfacetypes having contact angles θ₁ and θ₂. The contact angles in Table P arebelow the values expected from this equation, based on the purecomponent values θ₁ and θ₂, indicating that the surface was enriched bythe hydrophilic excipient.

TABLE P Contact angle of dry powder after centrifugation and dryingExcipient Contact angle (°) Bulk danazol 61.5 61.0 PVP K-15 41.8 40.4PVP 40T 48.8 47.0 Pluronic F127 34.0 34.0 DCA 19.9 17.8 SLS 7.0 PVP40T + Pluronic F127 42.0 37.5 PVP 40T + DCA 34.0 36.2 PVP 40T + SLS 14.613.2

Cyclic Stability Study

Cyclic Stability Study. Two week cyclic stability tests were undertakenunder harsh storage conditions for the three systems with the highestdissolution rates. Samples were analyzed each week to determine if thepotency, particle size, crystallinity, dissolution rate and morphologyhad changed with time. The concentrations of danazol in the threesystems were: 88.9% with SD (standard deviation) of 2.9% in PVPK-15+Danazol, 93.6% with SD of 1.4% in PVP 40T+Danazol and 89.6% with SDof 5.0% in PVP 40T+SDS+Danazol.

Redispersibility of the Dry Powder. The dry powders were redispersedinto 500 ml pure water. Changes over two weeks are shown in FIG. 10.Without ultrasound, the size of particles stabilized with PVP K-15increased from 9.7 μm to 25.5 μm after two weeks. However, after 15seconds sonication, the primary particle size decreased to 8 μm for bothsamples. For the PVP K-15 system, agglomeration of the dry particlesincreased with time. These agglomerates were broken into primaryparticles with ultrasound. The moisture in the container was minimal dueto desiccant.

X-Ray Diffraction. X-ray diffraction was used to study the crystallinityof the dry powders. As shown in FIG. 11 shows the diffraction profilesof danazol over 2 weeks.

Surface Area. FIG. 12 shows the surface area of danazol systems overtime. This result was in accord with the stability of the drug particlesize over time. FIG. 14 shows that danazol with PVP 40T+SLS has a smoothcrystal surface, but with PVP K-15 or PVP 40T it has a fluffy Surface,despite the similar crystallinities.

Dissolution Rates. The dissolution results are shown in FIG. 13. Thedissolution rate did not change over time, nor did other certainproperties of these drug powders, including the particle size andsurface area. For the two week cyclic stability study, high potencydanazol dry powders with PVP K-15, PVP 40T or PVP 40T and SDS asstabilizing excipients were very stable when desiccant was used toprevent to the particles from the moisture.

What is claimed is:
 1. A composition of poorly water soluble drugparticles having a drug-to-excipient ratio of greater than about 3:1; adissolution rate greater than about 70% drug dissolved about 3 timesfaster than the bulk drug; and a drug potency greater than about 66%. 2.The composition of claim 1 wherein the drug particles have a surfacearea and wherein the surface area is greater than about 2.5 m²/g, 5m²/g, 10 m²/g, 20 m²/g or 30 m²/g.
 3. The composition of claim 2,wherein the drug-to-excipient ratio is greater than about 5:1, 7:1 or10:1.
 4. The composition of claim 3, wherein the drug potency is about70%, 80%, 90% or 100%.
 5. The composition of claim 4, wherein the amountof drug dissolved is about 80%, 85%, 90%, 95% or 100%.
 6. Thecomposition of claim 5, wherein the dissolution occurs about 5, 7, 10,15, 20, 25 or 30 times faster than the bulk drug.
 7. The composition ofclaim 6, wherein the drug particles are produced by solutionprecipitation methods, anti-solvent precipitation, spray drying, sprayfreezing, evaporative precipitation into an aqueous solution, wetmilling, mechanical milling, or lyophilization.
 8. The composition ofclaim 7, wherein the drug particles are amorphous, crystalline orsemi-crystalline.
 9. A poorly water soluble drug particle composition,wherein the composition produced by evaporative precipitation into anaqueous solution and wherein said formulation having a drug-to-excipientratio greater than about 3:1.
 10. The composition of claim 9, whereinthe drug-to-excipient ratio is greater than about 5:1, 7:1 or 10:1. 11.The composition of claim 10, wherein the drug particles have a surfacearea and wherein the surface area is greater than about 2.5 m²/g, 5m²/g, 10 m²/g, 20 m²/g or 30 m²/g.
 12. The composition of claim 11,wherein the drug potency is about 66%, 70%, 80%, 90% or 100%.
 13. Thecomposition of claim 12, wherein the amount of drug dissolved is about80%, 85%, 90%, 95% or 100%.
 14. The composition of claim 13, wherein thedissolution occurs about 5, 7, 10, 15, 20, 25 or 30 times faster thanthe bulk drug.
 15. The composition of claim 14, wherein the drugparticles are amorphous, crystalline or semi-crystalline.
 16. A methodof producing drug formulations comprising the steps of: preparingstabilized drug particles in a suspension solution by evaporativeprecipitation into an aqueous solution; separating the particles fromthe suspension solution; and drying the resulting formulation to producea drug formulation having a drug potency of about 66%.
 17. The method ofclaim 16, wherein the drug particles are separated by centrifugation,settling, or filtering.
 18. The method of claim 16, wherein the drugparticles are lyophilized, vacuum dried, or spray dried.
 19. The methodof claim 16, wherein the drug-to-excipient ratio is greater than about3:1, 5:1, 7:1 or 10:1.
 20. The method of claim 19, wherein the drugparticles have a surface area and wherein the surface area is greaterthan about 2.5 m²/g, 5 m²/g, 10 m²/g, 20 m²/g or 30 m²/g.
 21. The methodof claim 20, wherein the drug potency is about 70%, 80%, 90% or 100%.22. The method of claim 21, wherein the amount of drug dissolved isabout 70%, 80%, 85%, 90%, 95% or 100%.
 23. The method of claim 22,wherein the dissolution occurs about 5, 7, 10, 15, 20, 25 or 30 timesfaster than the bulk drug.
 24. The pharmaceutical composition comprisingthe composition of claim
 1. 25. The pharmaceutical compositioncomprising the composition of claim
 9. 26. The method of claim 16,comprising a further step of formulating the particles forpharmaceutical administration.
 27. The method of claim 16, comprising afurther step of formulating the particles for pharmaceuticaladministration.